The kahalalide compounds are peptides isolated from a Hawaiian herbivorous marine species of mollusc, Elysia rufescens and its diet, the green alga Bryopsis. sp. Kahalalides A-F are described in Hamman et al., J. Am. Chem. Soc., 1993, 115, 5825-5826.
Kahalalide A-G are described in Hamann, M. et al., J. Org. Chem, 1996, 61, 6594-6600: “Kahalalides: bioactive peptides from a marine mollusk Elysia rufescens and its algal diet Bryopsis sp.”.
Kahalalide H and J are described in Scheuer P. J. et al., J. Nat. Prod. 1997, 60, 562-567: “Two acyclic kahalalides from the sacoglossan mollusk Elysia rufescens”. 
Kahalalide O is described in Scheuer P. J. et al., J. Nat. Prod. 2000, 63(1) 152-4: A new depsipeptide from the sacoglossan mollusk Elysia ornata and the green alga Bryopsis species”.
For kahalalide K, see Kan, Y. et al., J. Nat. Prod. 1999 62(8) 1169-72: “Kahalalide K: A new cyclic depsipeptide from the hawaiian green alga bryopsis species”.
For related reports, see also Goetz et al., Tetrahedron, 1999, 55; 7739-7746: “The absolute stereochemistry of Kahalalide F”; Albericio, F. et al. Tetrahedron Letters, 2000, 41, 9765-9769: “Kahalalide B. Synthesis of a natural cyclodepsipeptide”; Becerro et al. J. Chem. Ecol. 2001, 27(11), 2287-99: “Chemical defenses of the sarcoglossan mollusk Elysia rufescens and its host Alga bryopsis sp.”.
Of the kahalalide compounds, kahalalide F is the most promising because of its antitumoral activity. Its structure is complex, comprising six amino acids as a cyclic part, and an exocyclic chain of seven amino acids with a terminal fatty acid group. Its activity against in vitro cell cultures of human lung carcinoma A-549 and human colon carcinoma HT-29 were reported in EP 610 078. Kahalalide F has also demonstrated to have antiviral and antifungal properties.
Preclinical in vivo studies determined that the maximum tolerated dose (MTD) of Kahalalide F in female mice following a single bolus iv injection was to be 280 μg/kg. Whereas single doses just above the MTDiv were extremely toxic, with animals exhibiting signs of neurotoxicity followed by death, 280 μg/kg Kahalalide F could be administered repeatedly, according to a once daily times five schedule, without any apparent evidence of acute toxicity. See Supko, F. et al., Proceedings of the 1999 AACR NCI EORTC International Conference, abstract 315: “Preclinical pharmacology studies with the marine natural product Kahalalide F”.
WO 02 36145 describes pharmaceutical compositions containing kahalalide F and new uses of this compound in cancer therapy and is incorporated herein by reference in its entirety.
WO 03 33012, from which we claim priority, describes the clinical use in oncology of Kahalalide compounds and is incorporated herein by reference in its entirety.
GB 0304367, from which we also claim priority, describes the use of kahalalide compounds in the treatment of psoriasis and related ilnesses and is incorporated herein by reference in its entirety.
The synthesis and cytotoxic activities of natural and synthetic kahalalide compounds is described in WO 01 58934, which is incorporated herein by reference in its entirety. WO 01 58934 describes the synthesis of Kahalalide F and also of compounds with a similar structure in which the terminal fatty acid chain is replaced by other fatty acids.
There is still a need to provide further antitumoral compounds, in particular further Kahalalide compounds with improved properties.